Oxidation of heterocyclic aromatic nitrogen compounds



Patented Sept. 21, 1948 OXIDATION OF HETEROCYCLIC AROMATIO NITROGEN COMPOUNDS MarBsMneller, Dnmont, N. 1., minor to Allied- Chemical 8: Dye Corporation, New York, N. Ir, a corporation of New York No Drawing. Application November 2111944, Serial No. 564,553

This invention relates to the production of pyridine carboxylic acids by catalytic oxidation of heterocyclic aromatic nitrogen compounds having an oxidizable' organic grouping attached to the nitrogen-containingaromatic nucleus by one: or' more carbon-to-carbon linkages; more particularly it relates to the production of nicotin'ic 'acidfrom compoundsof the type described.

My co-pending application Serial No. 461,446,

new" Patent No. 2,436,660, flied October 9, 1942,

describes mprocessfor oxidation of heterocyclic aromatic nitrogencompounds of the type above described to pyridine-carboxylic acids by reactimhecompounds with sulfuric acid in the presenee era-relatively small amount of a selenium compound,

Mypresent invention-is in the nature of an improvement upon the process described in theabove identified co-pending application, which improvement permits a substantial reduction in the optimum temperature ranges employed inthe-oxidationof the heterocyclic aromatic nitrogen-compounds.

The object of this invention is, therefore, to provide a new and'improved process for the oxidation of heterocyclic aromatic nitrogen compounds havi n an oxidizable organic grouping att'mohed to" the nitrogen-containing aromatic nucleus by oneor more carbon-to-carbon link: ages:

In accordance with my invention an N-hetero- .aryi compound having an oxidizable organic grouping attached to the nitrogen-containing aromatic nucleus by one or more carbon-to-carbonliukages is oxidized to a pyridine carboxylic acid byreacting a solution of the compound in sulfuric acid, said solution containing a relatively small amount of a dissolved selenium compound, with nitric acid.

Oxidation of the N-heteroaryl compounds above described in accordance withthis invention-produces highly valuable pyridine carboxylic' acids-in excellent yields, Furthermore. the optimum temperature ranges for the oxidation are substantially lower than those employed in oxidining the same compound with sulfuric acid in tho-presence of the same catalyst. For example,

' oxidation of 3-picoline to nicotinic acid with sulfuricacid in the presence of a dissolved selenium compoundis preferably carried out at a temperature between 305 and 315 C., while oxidation of 3-picoline in the presence of such catalysts in accondanoe with this invention is most advantageously done at 250-to 260 C. Accordingly, my invention permits production of the desired 10cm. (01. zoo-295.5)

pyridine carb'oxyiic acids at=considerablylowen cost.

The term N-heteroaryl'compound'v" is em ployed throughout the specification andrclaimstm denote those heterocyclic compounds whiclrcontain in their structure a nucleus-- formed1bythe-.-

replacement of one group of an aromatic nucleus by a nitrogenatom.

My invention is applicable to the 05:

any N-heteroaryl compound havina, oxidize able organic groupingattached tothe nitrogen containing aromatic nucleus byone or car: bon-to-carbon linkages. 'l'huathe picolin'co. lutidines, collidines, quinoline. hydlmeqllinorlines, quinoline suifonic acids, quinaldine.,is'oquinoline, lepidine and nicotine may. be treatedin accordance withthis invention. Thohaturo of the product obtained depends upon the N- heteroaryl compoundoxidiaedand, in some upon the temperature at which the-oxidatio'nris,

carried out. Thus, oxidation? of 3-picolino or9- nicotine yields nicotinic acid. Oxidation; of: quinoline or a-hydroxy-quinoline at temperatures above 190 0 yields chiefly nicotinlc-acidabiltaat:

temperatures substantialiyvbelow this-valufi'duinv olinic acid is the principal product; Olddatiiinp! 2 -picoline yields picolinic acid. and oxidation? of 4-picoline yields isonicotinic acid: oxidation or. isoquinoline yields cinchomeronic. acid; Oxidation of quinaldine at temperatures above about- 190 C. yields chiefly pyridine-2,5-dicarbo1wlic acid, but oxidation of quinaldine at: temperatures substantially below this value yields Z-methyl pyridine-5,6-dlcarboxylic acid. A preferred embodiment of my invention involves the oxidation: of quinoline or 3-picoline to-nicotinic acid, since the quinoline and 3-picoline reactants are-available or potentially available in largeamounts Gilda the product obtained is the most valuable of the pyridine carboxylic acids at the present time; The N-heteroaryl. compoundstreated mayv be in' substantially pure condition, or in. crude form. as recovered from coal tar by conventional procedures.

The sulfuric acid employedis preferably concentrated sulfuric acid such as 66 B. acid. but more dilute acid such as B. acid may be used, or, less desirably, fuming sulfuric acid. The amount of sulfuric acid employed may vary considerably but should be sufllcient to both combine with the basic nitrogen atom of the N-heteroaryi compound and. maintain the compound in solu- 3 tion at the temperature of oxidation; generally between about 5 and about 8 mols of sulfuric acid per mol of N-heteroaryl compound to be treate is suitable.

The catalysts employed in accordance with this invention may be any of the catalysts described in the co-pending application hereinabove referred to.

A selenium catalyst of my co-pending application may be'incorporated in the reaction mix ture by adding uncombined selenium, selenium oxychloride, selenium oxybromide, selenium sulfoxide, selenium dioxide, or selenic or selenous.

acids or their salts to the reaction mixture. The selenium catalyst may advantageously be prepared by slowly adding a slight excess of sulfuric acid or, preferably, nitric acid to selenium and then boiling the mixture for about fifteen'minutes to form a selenium dioxide solution and effect removal of the excess acid. The amount of selenium catalyst employed may vary widely but generally between about 0.03 and about 0.3 gram atom of selenium per mol of N-heteroaryl compound treated is suitable.

The catalysts of the Teeters copending application Serial No. 461,417 filed October 9, 1942, may be utilized in conjunction with the selenium catalysts of the present invention. In such a case the particular mode of addition of the catalyst to the reaction mixture depends upon the nature of the catalytic material to be employed. Thus, for example, if a gaseous substance such as chlorine, hydrogen chloride or hydrogen bromide is to be employed as catalyst, it may be added to the reaction mixture by introducing the gas through a suitable distributor below the surface of the reaction mixture. In the case of a liquid substance such as free bromine, the catalysts may be slowly added to the reaction mixture, preferably with good agitation. In the case of a solid catalyst, such as iodine or metal halides such as sodium or potassium bromide, the entire amount of the catalysts to be employed may be added to the reaction mixture at the start of the reaction, but preferably the catalysts are gradually added to the mixture throughout the course of the oxidation. Among the materials preferably employed as catalysts along with the selenium compound are chlorine, bromine, iodine, hydrogen chloride, hydrogen bromide, hydrogen iodide, iodic acid and other iodine oxides, iodine monochloride and other mixed halogen compounds, alkali metal chlorides, bromides or iodides, or mixtures of such substances. A particularly suitable catalyst may be formed by the addition of a selenium compound soluble in sulfuric acid and an alkali metal bromide such as sodium or potassium bromide to the reaction mixture in proportions such that the amount of the selenium compound is equivalent to from 0.5 to about 2.0 atoms of selenium per atom of bromine contained in the bromide. The amount of halogen catalyst employed may vary widely but generally between about 0.5 and about 25% by weight of the N-heteroaryl compound treated is preferred.

The selenium catalyst, particularly when combined with a halogen catalyst, is eminently adapted for the oxidation of the alkyl substituted pyridines such as 3-picoline.

In carrying out the process of my invention, the N-heteroaryl compound to be oxidized may be dissolved in the sulfuric acid, the catalyst added, and the mixture then heated to reaction temperature; gradual addition of the nitric acid is th commenced and the addition of nitric acid continued until oxidation is substantially complete, which may be determined by analysis of a portion of the reaction mass or by a marked increase in the evolution of brown oxides of nitrogen. Nitric acid containing from about 50% to about 75% HNOa is preferably employed although acid of other concentrations may be used if desired.

The temperature at which the oxidation is carried outmay vary considerably, depending upon the N-heteroaryl compound treated, upon the catalyst employed and, in some cases, upon the desired pyridine carboxylic acid. The following table indicates optimum temperature ranges for carrying out various oxidations in accordance with preferred embodiments of my invention.

Optimum gfiggg Catalyst Product Teig glrggure C. Quinoline. Se Nicotinic Acid 250 to 270 Methyl pyridines... Se Corresponding Acid 250 to 260 In general it may be said that when employing a selenium catalyst for the oxidation of polynuclear N-heteroaryl compounds in accordance with a preferred embodiment of my invention, temperatures between 250 and 270 C. are most suitable, unless quinolinic acid or 2-methylpyridine-5, fi-dicarboxylic acid is to be produced, in which cases temperatures between about and about C. should be used. Oxidation of methyl pyridines is preferably carried out at 250 to 260 C. Broadly, temperatures anywhere between 100 and 300 C. will effect oxidation of the N-heteroaryl compounds in accordance with my invention.

While the method of carrying out the oxidation above described represents the preferred embodiment of my invention, the oxidation may also be carried out by gradually adding to sulfuric acid maintained at reaction temperature a solution containing the N-heteroaryl compound to be oxidized dissolved in the nitric acid, the catalyst being in solution, either in the nitric acid or in the sulfuric acid.

The pyridine carboxylic acid product obtained as a result of the oxidation may be recovered in any suitable manner. In the case of nicotinic acid, produced in accordance with the preferred embodiment of this invention, the acid reaction mixture containing sulfuric acid, nicotinic acid sulfate and the catalyst may be cooled to room temperature and poured into water or ice; the sulfuric acid may then be partially neutralized with an alkaline material such as ammonia and any precipitate which forms removed by filtration. The pH value of the solution may then be raised to between about 5 and about 7 by adding sufficient alkali, or by adding an excess of ammonia thereto and boiling until the solution becomes acid to litmus, and the nicotinate converted into copper nicotinate by reaction with copper sulfate; the copper nicotinate precipitate may be recovered by filtration and converted by reaction with sodium hydroxide into sodium nicotinate. Nicotinic acid is preferably recovered from the sodium nicotinate by the addition of an acid such as hydrochloric or sulfuric acid to the sodium nicotinate solution until the pH value thereof is between about 3 and about 4, preferably between about 3,4 and about 3,6, and cooling, since I have found maximum yields of nicotinic acid may thereby be obtained; a Brom auaeos Phenol Blue indicator maybe used in ldlilltlng the pII-value since the neutral point or mdicator to nieotinic acid, i. e. the point at which the indicator Just turns yellow, is within the traiizing, adiusting the pH value of the solution to between 1 and 2, preferably between 1.4 and 1.8,"and crystallizing the acid. Isonicotinic acid may be recovered from the reaction mixtureresulting from oxidation of 4-picoline by substantially the same manner that cinchomeronic acid is recovered except that the pH value 'of the partially neutralized solution should be adjusted to between sand 4, preferably between 3.4 and 3.6.

The following examples are illustrative of my invention. Amounts are given in parts by weight.

Example 1 735 parts of 93% sulfuric acid, 5 parts of selenium and 171 parts of quinoline were mixed and the mixture heated to between 260 and 270 C. Addition of 70% nitric acid to the mixture was then commenced; the nitric acid was added gradually over a period of 3% hours, during which time 605 parts of nitric acid were introduced, the reaction mixture being maintained beween 260 and 270 C. At the end of this time the reaction mixture was poured onto ice and suiiicient sodium hydroxide solution was added to bring the solution to a pH of about 10. The alkaline solution was agitated with activated carbon for ,9 hour, filtered, and acid added until the pH value of the solution had been lowered to 5; the solution was then again treated with activated carbon, filtered and the pH of the filtrate adjusted to between 6 and 7. The filtrate was then heated to between 85 and 90 C. and a solution of copper sulfate was slowly added thereto, after which the mixture was heated at 85 to 90 C. for about hour. Copper nicotinate thus formed was recovered by filtration.

Example 2 735 parts of 93% sulfuric acid, 3.9 parts of selenous acid, 4.76 parts of potassium bromide, and 128 parts of 3-picoline were mixed and the mixture heated to a temperature between 250 and 255 0. Addition of 70% nitric acid to the mixture was then commenced; the acid was added gradually over a period of 5% hours. during which time 430 parts were introduced, the temperature being maintained between 250 and 255 C. Upon completion of the reaction, copper nicotinate was recovered as described in Example 1.

Example 3 735 parts of sulfuric acid, 4.76 parts of potassium bromide. 3.2 parts of selenium and 93.1 parts of 2-picoline were mixed and the mixture heated to between 250 and 255 C. Addition of a mixture of 70% nitric acid and 36% hydrochloric acid to the mass was then commenced, the acid mixture containing 710 parts of nitric acid and 29.5 parts of hydrochloric acid; the mixture of acids was gradually added over a period of 4 hours. the-temperature being maintained between 250 and 255 C. At the end of 6 this time the reaction mixture was treated as de- 1. In the catalytic oxidation to a pyridine carboxylic acid 'of an N-heteroaryl compound containing a pyridine nucleus and containing an oxidizabie organic grouping attached to the scribed in Example 1 to recover copper picolinate.

nitrogen containing aromatic nucleus by at least one carbon-to-carbon linkage, the improvement which. comprises conducting the oxidation by reacting nitric acid with a solution containing the N-heteroaryl compound and a relatively small amount of a substance selected from the group H consisiting of selenium and a selenium compound dissolved in sulfuric acid, and recovering a compound containing v.the pyridine carboxylic acid radical.

2. In the catalytic oxidation to a pyridine carboxylic acid of .an N-heteroaryl compound containing a pyridine nucleus and containing an oxidiaable organic grouping attached to the nitrogen-containing aromatic nucleus by at least one carbon-to-carbon linkage, the improvement which comprises conducting the oxidation by reacting nitric acid with a solution containing the N-heteroaryl compound and relatively small amounts of a selenium compound and a halogen compound dissolved in sulfuric acid, and recovering a compound containing the pyridine carboxylic acid radical.

3. In the catalytic oxidation to a pyridine carboxylic acid of an N-heteroaryl compound containing a pyridine nucleus and containing an oxidizable organic grouping attached to the nitrogen containing aromatic nucleus by at least one carbon-to-carbon linkage, the improvement which comprises conducting the oxidation by reacting nitric acid with a solution containing the 'N-heteroaryl compound and relatively small.

containing between about 50% and about 75% j HNQ: to a solution of quinoline in concentrated sulfuric acid containing a relatively small amount of a selenium compound and an alkali metal bromide while maintaining the solution at a temperature between about 250 and about 270 C., and recovering a compound containing the nicotinic acid radical.

5. In the catalytic oxidation of 3-picoline to nicotinic acid, the improvement which comprises conducting the oxidation by adding nitric acid containing between about 50% and about 75% HNO: to a solution of 3-picoline in concentrated sulfuric acid containing a relatively small amount of 'a selenium compound while maintaining the solution at a temperature between about 250 and about 260 C., and recovering a compound containing the nicotinic acid radical.

6. In the catalytic oxidation of 3-picoline to nicotinic acid, the improvement which comprises conducting the oxidation by adding nitric acid 4 containing between about 50% and about 75% '1. In the catalytic oxidation of quinoline to nicotinic acid, the improvement which comprises conducting the oxidation by adding nitric acid containing between about 50% and about 75% HNO: to a solution of quinoline in concentrated sulfuric acid containing a relatively small amount of a selenium compound while maintaing the solution at a temperature between about 250 and 270 C., and recovering a compound containing the nicotinic acid radical.

8. In the catalytic oxidation of quinoline to nicotinic acid, the improvement which comprises conductingthe oxidation by adding nitric acid containing between about 50% and about 75% HNO; to a solution of quinoline in concentrated sulfuric acid containing a relatively small amount of a selenium compound and a halogen compound while maintaining the solution at a temperature between about 250 and about 270 C., and recovering a compound containing the nicotinic acid radical.

9. In the catalytic oxidation of isoquinoline to nitric acid containing between about and about HNO: to a solution of isoquinoline in concentrated sulfuric acid containing relatively small amounts of a selenium compound and a halogen compound while maintaining the solution at a temperature between about 250 and about 270 C., and recovering a compound containing the cinchomeronic acid radical.

MAX B. MUELLER. 

